Genetics of type 1 diabetes

Abstract

Genetic susceptibility to type 1 diabetes (T1D) has been a subject of intensive study for nearly four decades. This article will present the history of these studies, beginning with observations of the Human Leukocyte Antigen (HLA) association in the 1970s, through the advent of DNA-based genotyping methodologies, through recent large, international collaborations and genome-wide association studies. More than 40 genetic loci have been associated with T1D in multiple studies; however, the HLA region, with its multiple genes and extreme polymorphism at those loci, remains by far the greatest contributor to the genetic susceptibility to T1D. Even after decades of study, the complete story has yet to unfold, and exact mechanisms by which HLA and other associated loci confer T1D susceptibility remain elusive.

Figure 1.

Schematic representation of selected genes in the HLA region. Classical HLA genes are shown in black. Other T1D-associated genes are shown with patterned boxes. Gray boxes show genes not reported to be T1D-associated. Approximate boundaries of class I, class III, and class II regions are indicated by brackets.

Figure 2.

(A) Schematic representation of HLA class II and class I molecules. Protein domains are depicted as gray circles, plasma membrane is depicted by black ball and stick motifs, transmembrane regions are depicted as lines going through the plasma membrane, and the peptide antigen is depicted as a black diamond. (B) Schematic representation of the trimolecular complex. HLA molecule and peptide are depicted as in A; T-cell receptor is depicted as a gray Y-shape that contacts both the HLA molecule and the peptide antigen.

Figure 3.

Trans-encoded heterodimers. DR3 and DR4 haplotypes from the highly predisposing DR3/DR4 genotype are shown; putative high-T1D-risk heterodimers encoded in trans are circled.